15-42745214-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_173500.4(TTBK2):c.*581A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 156,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (1 hom.)
• Consequence: TTBK2 NM_173500.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0250

Genes affected

TTBK2 (HGNC:19141): (tau tubulin kinase 2) This gene encodes a serine-threonine kinase that putatively phosphorylates tau and tubulin proteins. Mutations in this gene cause spinocerebellar ataxia type 11 (SCA11); a neurodegenerative disease characterized by progressive ataxia and atrophy of the cerebellum and brainstem. [provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 15-42745214-T-A is Benign according to our data. Variant chr15-42745214-T-A is described in ClinVar as [Benign]. Clinvar id is 315970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00193 (292/151612) while in subpopulation EAS AF= 0.00503 (26/5172). AF 95% confidence interval is 0.00352. There are 0 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTBK2	NM_173500.4	c.*581A>T		3_prime_UTR_variant	15/15	ENST00000267890.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK2	ENST00000267890.11	c.*581A>T		3_prime_UTR_variant	15/15	5	NM_173500.4	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 292 AN: 151496 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0000959

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00434

GnomAD4 exome AF: 0.00312 AC: 15 AN: 4802 Hom.: 1 Cov.: 0 AF XY: 0.00327 AC XY: 8 AN XY: 2444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00578

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00193 AC: 292 AN: 151612 Hom.: 0 Cov.: 32 AF XY: 0.00181 AC XY: 134 AN XY: 74100

Gnomad4 AFR AF: 0.00208

Gnomad4 AMR AF: 0.00354

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00503

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.0000959

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00430

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00209

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.045
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs575564250; hg19: chr15-43037412; COSMIC: COSV51160915; COSMIC: COSV51160915;